Kinase inhibitors

ABSTRACT

The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and/or inhibit abnormal cell proliferation.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of Ser. No. 12/377,098, filed Feb.10, 2009, which is a §371 National Stage of PCT/US2007/075669, filedAug. 10, 2007, which claims the benefit of U.S. Provisional ApplicationSer. No. 60/822,105, filed Aug. 11, 2006, each of which is herebyincorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds capable of modulating,regulating and/or inhibiting tyrosine kinase signal transduction. Thepresent invention is also directed to methods of regulating, modulatingor inhibiting tyrosine kinases, whether of the receptor or non-receptorclass, for the prevention and/or treatment of disorders related tounregulated tyrosine kinase signal transduction, including cell growth,metabolic, and blood vessel proliferative disorders.

2. Description of the Related Art

Protein tyrosine kinases (PTKs) comprise a large and diverse class ofproteins having enzymatic activity. The PTKs play an important role inthe control of cell growth and differentiation.

For example, receptor tyrosine kinase mediated signal transduction isinitiated by extracellular interaction with a specific growth factor(ligand), followed by receptor dimerization, transient stimulation ofthe intrinsic protein tyrosine kinase activity and phosphorylation.Binding sites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic homeostasis, and responses tothe extracellular microenvironment).

With respect to receptor tyrosine kinases, it has been shown also thattyrosine phosphorylation sites function as high-affinity binding sitesfor SH2 (src homology) domains of signaling molecules. Severalintracellular substrate proteins that associate with receptor tyrosinekinases (RTKs) have been identified. They may be divided into twoprincipal groups: (1) substrates which have a catalytic domain; and (2)substrates which lack such domain but serve as adapters and associatewith catalytically active molecules. The specificity of the interactionsbetween receptors or proteins and SH2 domains of their substrates isdetermined by the amino acid residues immediately surrounding thephosphorylated tyrosine residue. Differences in the binding affinitiesbetween SH2 domains and the amino acid sequences surrounding thephosphotyrosine residues on particular receptors are consistent with theobserved differences in their substrate phosphorylation profiles. Theseobservations suggest that the function of each receptor tyrosine kinaseis determined not only by its pattern of expression and ligandavailability but also by the array of downstream signal transductionpathways that are activated by a particular receptor. Thus,phosphorylation provides an important regulatory step which determinesthe selectivity of signaling pathways recruited by specific growthfactor receptors, as well as differentiation factor receptors.

Aberrant expression or mutations in the PTKs have been shown to lead toeither uncontrolled cell proliferation (e.g. malignant tumor growth) orto defects in key developmental processes. Consequently, the biomedicalcommunity has expended significant resources to discover the specificbiological role of members of the PTK family, their function indifferentiation processes, their involvement in tumorigenesis and inother diseases, the biochemical mechanisms underlying their signaltransduction pathways activated upon ligand stimulation and thedevelopment of novel drugs.

Tyrosine kinases can be of the receptor-type (having extracellular,transmembrane and intracellular domains) or the non-receptor type (beingwholly intracellular).

The RTKs comprise a large family of transmembrane receptors with diversebiological activities. The intrinsic function of RTKs is activated uponligand binding, which results in phosphorylation of the receptor andmultiple cellular substrates, and subsequently in a variety of cellularresponses.

At present, at least nineteen (19) distinct RTK subfamilies have beenidentified. One RTK subfamily, designated the HER subfamily, is believedto be comprised of EGFR, HER2, HER3 and HER4. Ligands to the Hersubfamily of receptors include epithelial growth factor (EGF), TGF-α,amphiregulin, HB-EGF, betacellulin and heregulin.

A second family of RTKs, designated the insulin subfamily, is comprisedof the INS-R, the IGF-1R and the IR-R. A third family, the “PDGF”subfamily includes the PDGF α and β receptors, CSFIR, c-kit and FLK-II.Another subfamily of RTKs, identified as the FLK family, is believed tobe comprised of the Kinase insert Domain-Receptor fetal liver kinase-1(KDR/FLK-1), the fetal liver kinase 4 (FLK-4) and the fms-like tyrosinekinase 1 (flt-1). Each of these receptors was initially believed to bereceptors for hematopoietic growth factors. Two other subfamilies ofRTKs have been designated as the FGF receptor family (FGFR1, FGFR2,FGFR3 and FGFR4) and the Met subfamily (c-met and Ron).

Because of the similarities between the PDGF and FLK subfamilies, thetwo subfamilies are often considered together. The known RTK subfamiliesare identified in Plowman et al, 1994, DN&P 7(6): 334-339, which isincorporated herein by reference.

The non-receptor tyrosine kinases represent a collection of cellularenzymes which lack extracellular and transmembrane sequences. Atpresent, over twenty-four individual non-receptor tyrosine kinases,comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70,Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, theSrc subfamily of non-receptor tyrosine kinases is comprised of thelargest number of PTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck,Fgr and Yrk. The Src subfamily of enzymes has been linked tooncogenesis. A more detailed discussion of non-receptor tyrosine kinasesis provided in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporatedherein by reference.

Many of the tyrosine kinases, whether an RTK or non-receptor tyrosinekinase, have been found to be involved in cellular signaling pathwaysleading to cellular signal cascades leading to pathogenic conditions,including cancer, psoriasis and hyper immune response.

In view of the surmised importance of PTKs to the control, regulationand modulation of cell proliferation the diseases and disordersassociated with abnormal cell proliferation, many attempts have beenmade to identify receptor and non-receptor tyrosine kinase “inhibitors”using a variety of approaches, including the use of mutant ligandssoluble receptors and antibodies RNA ligands and tyrosine kinaseinhibitors.

More recently, attempts have been made to identify small molecules whichact as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclicor heterocyclic aryl compounds, vinylene-azaindole derivatives and1-cyclopropyl-4-pyridyl-quinolones have been described generally astyrosine kinase inhibitors. Styryl compounds, styryl-substituted pyridylcompounds certain quinazoline derivatives seleoindoles and selenides,tricyclic polyhydroxylic compounds and benzylphosphonic acid compoundshave been described as compounds for use as tyrosine kinase inhibitorsfor use in the treatment of cancer.

The identification of effective small compounds which specificallyinhibit signal transduction by modulating the activity of receptor andnon-receptor tyrosine kinases to regulate and modulate abnormal orinappropriate cell proliferation is therefore desirable and one objectof this invention.

Finally, certain small compounds are disclosed in U.S. Pat. Nos.5,792,783; 5,834,504; 5,883,113; 5,883,116 and 5,886,020 as useful forthe treatment of diseases related to unregulated TKS transduction. Seealso, U.S. Pat. Nos. 6,541,504; 6,559,173; 6,765,012; 6,747,025;6,699,863; 7,005,444; 7,015,220 and 7,060,844. These patents are herebyincorporated by reference in its entirety for the purpose of disclosingstarting materials and methods for the preparation thereof, screens andassays to determine a claimed compound's ability to modulate, regulateand/or inhibit cell proliferation, indications which are treatable withsaid compounds, formulations and routes of administration, effectivedosages, etc.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to organic molecules capable ofmodulating, regulating and/or inhibiting tyrosine kinase signaltransduction. Such compounds are useful for the treatment of diseasesrelated to unregulated TKS transduction, including cell proliferativediseases such as cancer, atherosclerosis, restenosis, metabolic diseasessuch as diabetes, inflammatory diseases such as psoriasis and chronicobstructive pulmonary disease, vascular proliferative disorders such asdiabetic retinopathy, age-related macular degeneration and retinopathyof prematurity, autoimmune diseases and transplant rejection.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the general formulas I and II below are useful as kinaseinhibitors. As such compounds of formula I will be useful for treatingdiseases related to unregulated tyrosine kinase signal transduction, forexample, cancer, blood vessel proliferative disorders, fibroticdisorders, and neurodegenerative diseases. In particular compounds ofthe present invention are useful for the treatment of mesangial cellproliferative disorders and metabolic diseases, diabetic retinopathy,age-related macular degeneration, retinopathy of prematurity, arthritis,restenosis, hepatic cirrhosis, atherosclerosis, psoriasis, diabetesmellitus, wound healing, inflammation and neurodegenerative diseases.

Wherein substitutents listed are illustrated but not limited to theillustrative list set forth below:

-   -   wherein X is selected from the group consisting of C═O, C═S,        CR⁴R⁵, O, S, NH, and NR⁴;    -   Z is selected from the group consisting of hydrogen, C₁ to C₈        alkyl, phenyl, hydroxymethyl, —CH₂—N(—CH₂CH₂WCH₂CH₂—), COCH₃,        CH₂CH₂OH, and CH₂CH₂CH₂OH;    -   W is selected from the group consisting of O, S, CH₂ and NCH₃;    -   R¹ is selected from the group consisting of hydrogen and CH₃;    -   R³ is selected from the group consisting of hydrogen, C₁ to C₈        alkyl, phenyl, hydroxymethyl, COCH₃, CH₂CH₂OH, CH₂CH₂CH₂OH and        [C(R²)₂]_(c)N(R²)₂, wherein R² is selected from the group        consisting of hydrogen, halogen, NO₂, CN, C₁ to C₄ alkyl or        aryl, and N(R²)₂ may form a 3 to 7 membered heterocyclic ring,        for example pyrrolidine, 3-fluoropyrrolidine, piperidine,        4-fluoropiperidine, N-methylpiperazine, morpholine,        2,6-dimethylmorpholine, thiomorpholine; and said heterocyclic        ring may be substituted with one or more of R²; and [C(R²)₂]_(c)        may form a 3 to 7 membered carbocyclic or heterocyclic ring;    -   R⁴ and R⁵ may be selected from the group consisting of hydrogen,        halogen, NO₂, CN, C₁ to C₈ alkyl and aryl; or CR⁴R⁵ may form a 3        to 7 membered carbocyclic or heterocyclic ring;    -   A is 3 to 7 membered heterocyclic ring, e.g., A is a 5 or 6        membered heteroaryl radical represented by formula III below:

-   -   wherein said heteroaryl radical is selected from the group        consisting of:

-   -   wherein R is selected from the group consisting of hydrogen,        halogen, C₁ to C₈ alkyl, CF₃, OCF₃, OCF₂H, CH₂CN, CN, SR²,        (CR⁷R⁸)_(c)C(O)OR², C(O)N(R²)₂, (CR⁷R⁸)_(c)OR², HNC(O)R²,        HN—C(O)OR², C(O)NR²(CR⁷R⁸)_(c)N(R²)₂, NR²C(O)(CR⁷R⁸)_(c)N(R²)₂,        (CR⁷R⁸)_(c)OC(O)(CR⁷R⁸)_(c)N(R²)₂, (CR⁷R⁸)_(c)N(R²)₂,        SO₂(CR⁷R⁸)_(c)N(R²)₂, OP(O)(OR²)₂, OC(O)OR², OCH₂O, HN—CH═CH,        —N(COR²)CH₂CH₂, HC═N—NH, N═CH—S, O(CR⁷R⁸)_(d)—R⁶, (CR⁷R⁸)_(c)—R⁶        and (CR⁷R⁸)_(c)NR²(CR⁷R⁸)_(d)R⁶ wherein R⁶ is selected from the        group consisting of halogen, 3-fluoropyrrolidinyl, piperidinyl,        4-fluoropiperidinyl, N-methylpiperazinyl,        2,6-dimethylmorpholinyl, 3-fluoropiperidinyl, 2-pyridinyl,        3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl        isonipecotate, N-(2-methoxyethyl)-N-methylamyl,        1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl,        piperazinyl-2-one, piperazinyl, N-(2-methoxyethyl)ethylaminyl,        thiomorpholinyl, heptamethyleneiminyl,        1-piperazinylcarboxaldehyde,        2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one,        N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl,        N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl,        nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl,        3-acetamidopyrrolidinyl, trans-decahydroisoquinolinyl,        cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl,        3-(diethylamino)pyrrolidinyl,        1,4-dioxa-8-azaspiro[4.5]decaninyl,        1-(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl,        4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl,        3-picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl,        1-(2-pyrimidyl)-piperazinyl, 1-(2-pyrazinyl)-piperazinyl,        2-methylaminomethyl-1,3-dioxolane,        2-(N-methyl-2-aminoethyl)-1,3-dioxolane,        3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl,        tetrahydrofurfurylaminyl, 4-aminotetrahydropyran,        2-amino-1-methoxybutane, 2-methoxyisopropylaminyl,        1-(3-aminopropyl)imidazole, histamyl,        N,N-diisopropylethylenediaminyl, 1-benzyl-3-aminopyrrolidyl        2-(aminomethyl)-5-methylpyrazinyl,        2,2-dimethyl-1,3-dioxolane-4-methanaminyl,        (R)-3-amino-1-N-BOC-pyrrolidinyl,        4-amino-1,2,2,6,6-pentamethylpiperidinyl,        4-aminomethyltetrahydropyran, ethanolamine and alkyl-substituted        derivatives thereof; provided said alkyl or phenyl radicals may        be substituted with one or two halo, hydroxy or lower alkyl        amino radicals or said alkyl radicals may include enchained        nitrogen or oxygen atoms, i.e. oxa or imino radicals, as, for        example, in polyethylene(oxy)radicals and wherein R⁷ and R⁸ may        be selected from the group consisting of H, hydroxyl, halogen,        e.g. F, and C₁ to C₄ alkyl and CR⁷R⁸ may form a carbocyclic ring        of from 3 to 6 carbons;

-   -   X′ is selected from the group consisting of and    -   B may be selected from the group consisting of hydrogen,        hydroxy, C₁ to C₈ alkyl, aryl and CR⁴R⁵ wherein CR⁴R⁵ forms a 3        to 7 membered carbocyclic or heterocyclic ring, e.g., B may be a        5 or 6 membered aryl radical represented by formula III below:

-   -   wherein said aryl is selected from the group consisting of:

-   -   a is 0 or an integer of from 1 to 5, preferably 1 to 3;    -   c is 0 or an integer of from 1 to 4,    -   d is an integer of from 2 to 5;    -   the wavy line represents an E or Z bond and pharmaceutically        acceptable salts thereof.

Preferably Z, R¹ and R³ are H.

Preferably X′ is selected from the group consisting ofPreferably B is selected from the group consisting of 5-memberedheterocyclic aryl radicals and 6-membered carbocyclic aryl radicals.More preferably, X is

More preferably, X′ is

More preferably, B is a 5-membered heterocyclic aryl radical wherein theheterocyclic ring comprises one oxygen or sulfur atom or two nitrogenatoms.More preferably, said heterocyclic aryl radical is substituted with alower alkyl group or a halogen radical.In another embodiment, B is phenyl and said phenyl radical may besubstituted with a lower alkyl radical.Preferably a is 1 or 2 and at least one R is H or OH or a is 1 and R isselected from the group consisting of carboxylic acid radicals, and 5 or6 membered heterocyclic radicals wherein the heterocyclic ring includesa first enchained nitrogen atom and optionally, an enchained oxygen atomor a second enchained nitrogen atom.Preferably R includes a carboxylic acid radical which is covalentlybonded to a phenyl group through a polymethylene group, e.g. anethylenyl or a propylenyl group.Preferably R includes a heterocyclic ring which is directly bonded tothe phenyl group or indirectly through a polymethylene group wherein, ineither case, said bond is through an enchained nitrogen atom in saidheterocyclic ring.More preferably, said heterocyclic ring is selected from the groupconsisting of pyrrolidine, morpholine, piperazine and piperidine andsaid heterocyclic ring is substituted with a lower alkyl or a hydroxylradical.

R may be

R is

In another embodiment, B is selected from the group consisting of furyl,thienyl, pyrazole and imidazole.The following abbreviations may be used throughout this specification.

“Ac” refers to acetyl.

“Ar” refers to aryl.

“Tf” refers to triflate.

“Me” refers to methyl.

“Et” refers to ethyl.

“tBu” refers to t-butyl.

“iPr” refers to I-propyl.

“Ph” refers to phenyl.

“Pharmaceutically acceptable salt” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Alkyl” refers to a straight-chain, branched or cyclic saturatedaliphatic hydrocarbon. Preferably, the alkyl group has 1 to 12 carbons.More preferably, it is a lower alkyl of from 1 to 7 carbons, mostpreferably 1 to 4 carbons. Typical alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl andthe like. The alkyl group may be optionally substituted with one or moresubstituents are selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkenyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon group containing at least one carbon-carbon double bond.Preferably, the alkenyl group has 1 to 12 carbons. More preferably it isa lower alkenyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.The alkenyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkynyl” refers to a straight-chain, branched or cyclic unsaturatedhydrocarbon containing at least one carbon-carbon triple bond.Preferably, the alkynyl group has 1 to 12 carbons. More preferably it isa lower alkynyl of from 1 to 7 carbons, most preferably 1 to 4 carbons.The alkynyl group may be optionally substituted with one or moresubstituents selected from the group consisting of hydroxyl, cyano,alkoxy, ═O, ═S, NO₂, halogen, dimethyl amino, and SH.

“Alkoxyl” refers to an “O-alkyl” group.

“Aryl” refers to an aromatic group which has at least one ring having aconjugated pi electron system and includes carbocyclic aryl,heterocyclic aryl and biaryl groups. The aryl group may be optionallysubstituted with one or more substituents selected from the groupconsisting of halogen, trihalomethyl, hydroxyl, SH, OH, NO₂, amine,thioether, cyano, alkoxy, alkyl, and amino.

“Alkaryl” refers to an alkyl that is covalently joined to an aryl group.Preferably, the alkyl is a lower alkyl.

“Carbocyclic aryl” refers to an aryl group wherein the ring atoms arecarbon.

“Heterocyclic aryl” refers to an aryl group having from 1 to 3heteroatoms as ring atoms, the remainder of the ring atoms being carbon.Heteroatoms include oxygen, sulfur, and nitrogen. Thus, heterocyclicaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkylpyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like.

“Hydrocarbyl” refers to a hydrocarbon radical having only carbon andhydrogen atoms. Preferably, the hydrocarbyl radical has from 1 to 20carbon atoms, more preferably from 1 to 12 carbon atoms and mostpreferably from 1 to 7 carbon atoms.

“Substituted hydrocarbyl” refers to a hydrocarbyl radical wherein one ormore, but not all, of the hydrogen and/or the carbon atoms are replacedby a halogen, nitrogen, oxygen, sulfur or phosphorus atom or a radicalincluding a halogen, nitrogen, oxygen, sulfur or phosphorus atom, e.g.fluoro, chloro, cyano, nitro, hydroxyl, phosphate, thiol, etc.

“Amide” refers to —C(O)—NH—R′, wherein R′ is alkyl, aryl, alkylaryl orhydrogen.

“Thioamide” refers to —C(S)—NH—R′, wherein R′ is alkyl, aryl, alkylarylor hydrogen.

“Amine” refers to a —N(R″)R′″ group, wherein R″ and R′″ areindependently selected from the group consisting of alkyl, aryl, andalkylaryl.

“Thioether” refers to —S—R″, wherein R″ is alkyl, aryl, or alkylaryl.

“Sulfonyl” refers to —S(O)₂—R″″, where R″″ is aryl, C(CN)═C-aryl, CH₂CN,alkyaryl, sulfonamide, NH-alkyl, NH-alkylaryl, or NH-aryl.

-   -   Illustrative routes to compounds of the present invention are        illustrated in Schemes I, II, III, IV and V set forth below and        are not intended to limit the scope of the invention.

-   -   Wherein IVa & IVb are specific embodiments of Formula II in        which X═CH₂;

-   -   Wherein Ia of Scheme II and Ib of Scheme III are specific        embodiments of Formula I in which

-   -   Wherein X in Scheme IV represents X in Formula II, Ar₂ of Scheme        IV represents A in Formula II, and COAr₁ of Scheme IV represents        X′B in Formula II.

-   -   Wherein X of Scheme V represents X in Formula I, COAr₁ of Scheme        V represents X′B of Formula I

Specific Compounds of the invention include:

-   -   Molstructure

The present invention is further directed to pharmaceutical compositionscomprising a pharmaceutically effective amount of the above-describedcompounds and a pharmaceutically acceptable carrier or excipient. Such acomposition is believed to modulate signal transduction by a tyrosinekinase, either by inhibition of

catalytic activity, affinity to ATP or ability to interact with asubstrate.

More particularly, the compositions of the present invention may beincluded in methods for treating diseases comprising proliferation,fibrotic or metabolic disorders, for example cancer, fibrosis,psoriasis, atherosclerosis, arthritis, and other disorders related toabnormal vasculogenesis and/or angiogenesis, such as diabeticretinopathy.

The present invention relates to compounds capable of regulating and/ormodulating tyrosine kinase signal transduction and more particularlyreceptor and non-receptor tyrosine kinase signal transduction.

Receptor tyrosine kinase mediated signal transduction is initiated byextracellular interaction with a specific growth factor (ligand),followed by receptor dimerization, transient stimulation of theintrinsic protein tyrosine kinase activity and phosphorylation. Bindingsites are thereby created for intracellular signal transductionmolecules and lead to the formation of complexes with a spectrum ofcytoplasmic signaling molecules that facilitate the appropriate cellularresponse (e.g., cell division, metabolic effects and responses to theextracellular microenvironment).

It has been shown that tyrosine phosphorylation sites in growth factorreceptors function as high-affinity binding sites for SH2 (src homology)domains of signaling molecules. Several intracellular substrate proteinsthat associate with receptor tyrosine kinases have been identified. Theymay be divided into two principal groups: (1) substrates which have acatalytic domain; and (2) substrates which lack such domain but serve asadapters and associate with catalytically active molecules. Thespecificity of the interactions between receptors and SH2 domains oftheir substrates is determined by the amino acid residues immediatelysurrounding the phosphorylated tyrosine residue. Differences in thebinding affinities between SH2 domains and the amino acid sequencessurrounding the phosphotyrosine residues on particular receptors areconsistent with the observed differences in their substratephosphorylation profiles. These observations suggest that the functionof each receptor tyrosine kinase is determined not only by its patternof expression and ligand availability but also by the array ofdownstream signal transduction pathways that are activated by aparticular receptor. Thus, phosphorylation provides an importantregulatory step which determines the selectivity of signaling pathwaysrecruited by specific growth factor receptors, as well asdifferentiation factor receptors.

Tyrosine kinase signal transduction results in, among other responses,cell proliferation, differentiation and metabolism. Abnormal cellproliferation may result in a wide array of disorders and diseases,including the development of neoplasia such as carcinoma, sarcoma,leukemia, glioblastoma, hemangioma, psoriasis, arteriosclerosis,arthritis and diabetic retinopathy (or other disorders related touncontrolled angiogenesis and/or vasculogenesis, e.g. maculardegeneration).

This invention is therefore directed to compounds which regulate,modulate and/or inhibit tyrosine kinase signal transduction by affectingthe enzymatic activity of the RTKs and/or the non-receptor tyrosinekinases and interfering with the signal transduced by such proteins.More particularly, the present invention is directed to compounds whichregulate, modulate and/or inhibit the RTK and/or non-receptor tyrosinekinase mediated signal transduction pathways as a therapeutic approachto cure many kinds of solid tumors, including but not limited tocarcinoma, sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma,astrocytoma, melanoma and myoblastoma. Indications may include, but arenot limited to brain cancers, bladder cancers, ovarian cancers, gastriccancers, pancreas cancers, colon cancers, blood cancers, lung cancersand bone cancers.

All references cited herein are hereby incorporated by reference intheir entirety.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof.

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 2. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 3. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 4. A pharmaceuticalcomposition comprising at least one compound of claim 1 or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 5. A pharmaceutical compositioncomprising the compound of claim 2 or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.
 6. Apharmaceutical composition comprising the compound of claim 3 or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.